The present invention relates to a method for the solid phase synthesis of an amine, more particularly, the present invention relates to a method of synthesis of primary and secondary amines and .alpha.-amino esters useful as pharmaceutical agents.
Most of the existing resin attachment strategies used in solid phase organic synthesis (SPOS) have been determined by those specialties such as peptide, oligosaccharide, and oligonucleotide synthesis which have had the longest history in successful utilization of SPOS. For example, there are many resin attachment strategies for carboxylic acids that are attributable to solid phase peptide synthesis (Merrifield R. B., J. Am. Chem. Soc., 1963;85:2149; Steward J. M., Young J. D., Solid Phase Peptide Synthesis, Pierce Chemical Co., Rockford, Ill. 1984:9-14). Similarly oligosaccharide chemistry has provided methods to attach alcohols to resins by forming an ether linkage (Gait M. J., ed., Oligonuclentide Synthesis, IRL Press, Oxford, 1984; Frechet J. M. J., in Polymer-Supported Synthesis of Oligosaccharides, P. Hodge and D. C. Sherrington, eds., Wiley, New York: 1980:407-34). Recently, solid phase methodology has been applied to the synthesis of a wide variety of non-oligomeric molecules (Terrett N. K., Gardner M., Gordon D. W., Kobylecki R. J., Steele J., Tetrahedron, 1995;51:8135; Thompson L. A., Ellman J. A., Chem. Rev., 1996;96:555) but often the synthesis of such small organic molecules is restricted by the availability of linking strategies. A number of articles describing new resin linker strategies, including tetrahydro-pyranyl- (Thompson L. A., Ellman J. A., Tetrahedron Lett., 1994;35:9333), silyl- (Routledge A., Wallis M. P., Ross K. C., Fraser W., Bioorg. Med. Chem. Lett., 1995;5:2059; Plunkett M. J., Ellman J. A., J Org. Chem., 1995;60:6006; Randolph J. T., McClure K. F., Danishefsky S. J., J. Am. Chem. Soc., 1995;117:5712), sulfonyl- (Backes B. J., Virgilio A. A., Ellman J. A., J. Am. Chem. Soc., 1996;118:3055; Beaver K. A., Siegmund A. C., Spear K., Tetrahedron Lett., 1996;37:1145), benzyloxycarbonyl- (Pande C. S., Gupta N., Bhardwaj A., J. Appl. Polym. Sci., 1995;56:1127; Hauske J. R., Dorff P., Tetrahedron Lett., 1995;36:1589), and ADCC-linked solid supports (Bannwarth W., Huebscher, Barner R. W., Bioorg. Med. Chem. Lett., 1996;6:1525) have been published.
The object of the present invention is the use of a resin linker to which amino groups may be anchored for solid phase syntheses of a variety of heterocyclic molecules. Desirable properties of the linker include stability to strongly basic conditions, temperatures as high as 100.degree. C., and strong nucleophiles. Lastly, the linker should be cleaved under reasonably mild conditions.
We have found that the solid phase equivalent of a tertiary-butoxy carbonyl (t-Boc) protecting group fulfill these requirements. Thus, resin bound tertiary alcohols have been prepared by a two step synthesis from polystyrene-divinylbenzene (Wang S. S., Merrifield R. B., J. Am. Chem. Soc., 1969;91:6488) and chloromethylpolystyrene-divinylbenzene (Merrifield resin) (Wang S. S., J. Org. Chem., 1975;40:1235). These have been elaborated to a phenyl carbonate derivative and reacted with hydrazine to give a solid supported tert-alkoxycarbonylhydrazide which is used in the synthesis of C-terminal hydrazides of peptides. The use of these literature methods in the Boc-like anchoring of amines to solid supports has not reported, presumably because of difficulties achieving quantitative loading of amines via the tert-alkyl-phenylcarbonate moiety which is a relatively unreactive acylating agent.